Abstract
Filamentous fungi produce diverse secondary metabolites (SMs) essential to their ecology and adaptation. Although each SM is typically produced by only a handful of species, global SM production is governed by widely conserved transcriptional regulators in conjunction with other cellular processes, such as development. We examined the interplay between the taxonomic narrowness of SM distribution and the broad conservation of global regulation of SM and development in Aspergillus, a diverse fungal genus whose members produce well-known SMs such as penicillin and gliotoxin. Evolutionary analysis of the 2,124 genes comprising the 262 SM pathways in four Aspergillus species showed that most SM pathways were species-specific, that the number of SM gene orthologs was significantly lower than that of orthologs in primary metabolism, and that the few conserved SM orthologs typically belonged to non-homologous SM pathways. RNA sequencing of two master transcriptional regulators of SM and development, veA and mtfA, showed that the effects of deletion of each gene, especially veA, on SM pathway regulation were similar in A. fumigatus and A. nidulans, even though the underlying genes and pathways regulated in each species differed. In contrast, examination of the role of these two regulators in development, where 94% of the underlying genes are conserved in both species showed that whereas the role of veA is conserved, mtfA regulates development in the homothallic A. nidulans but not in the heterothallic A. fumigatus. Thus, the regulation of these highly conserved developmental genes is divergent, whereas–despite minimal conservation of target genes and pathways–the global regulation of SM production is largely conserved. We suggest that the evolution of the transcriptional regulation of secondary metabolism in Aspergillus represents a novel type of regulatory circuit rewiring and hypothesize that it has been largely driven by the dramatic turnover of the target genes involved in the process.
Highlights
Filamentous fungi produce diverse repertoires of small molecules known as secondary metabolites (SMs) [1]
To gain insight into the evolution of the regulatory circuit governing secondary metabolism and development, we examined the evolution of the genes and pathways underlying these processes as well as the evolution of their transcriptional regulation in the filamentous fungal genus Aspergillus, a prolific and important producer of secondary metabolites
The regulation of highly conserved developmental genes is divergent. These results point to a new type of rewiring that has occurred during the evolution of the regulatory circuit governing secondary metabolism and development in Aspergillus in which conserved regulators control a conserved biological process, even though the underlying genes and pathways that make up the biological process are not themselves conserved
Summary
Filamentous fungi produce diverse repertoires of small molecules known as secondary metabolites (SMs) [1]. The genes involved in fungal SM pathways are often physically linked in the genome, forming contiguous SM gene clusters [13] These gene clusters are typically characterized by a backbone gene, such as those encoding nonribosomal peptide synthetases (NRPSs), polyketide synthases (PKSs), hybrid NRPS-PKS enzymes, and prenyltransferases, whose protein products are responsible for synthesizing the proto-SM. The gene cluster responsible for the synthesis of the mycotoxin gliotoxin in the opportunistic human pathogen Aspergillus fumigatus contains 13 genes including a non-ribosomal peptide synthase (gliP), multiple tailoring enzymes (gliI, gliJ, gliC, gliM, gliG, gliN, gliF), a transporter gene (gliA), a transcription factor (gliZ), and a gliotoxin oxidase gene that protects the fungus from the harmful effects of gliotoxin (gliT) [14,15]
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